An ACE2-blocking antibody confers broad neutralization and protection against Omicron and other SARS-CoV-2 variants of concern

Wenjuan Du, Daniel L. Hurdiss, Dubravka Drabek, Anna Z. Mykytyn, Franziska K. Kaiser, Mariana González-Hernández, Diego Muñoz-Santos, Mart M. Lamers, Rien van Haperen, Wentao Li, Ieva Drulyte, Chunyan Wang, Isabel Sola, Federico Armando, Georg Beythien, Malgorzata Ciurkiewicz, Wolfgang Baumgärtner, Kate Guilfoyle, Tony Smits, Joline van der LeeFrank J.M. van Kuppeveld, Geert van Amerongen, Bart L. Haagmans, Luis Enjuanes, Albert D.M.E. Osterhaus, Frank Grosveld, Berend Jan Bosch*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

7 Citations (Scopus)

Abstract

The ongoing evolution of SARS-CoV-2 has resulted in the emergence of Omicron, which displays notable immune escape potential through mutations at key antigenic sites on the spike protein. Many of these mutations localize to the spike protein ACE2 receptor binding domain, annulling the neutralizing activity of therapeutic antibodies that were effective against other variants of concern (VOCs) earlier in the pandemic. Here, we identified a receptor-blocking human monoclonal antibody, 87G7, that retained potent in vitro neutralizing activity against SARS-CoV-2 variants including the Alpha, Beta, Gamma, Delta, and Omicron (BA.1/BA.2) VOCs. Using cryo-electron microscopy and site-directed mutagenesis experiments, we showed that 87G7 targets a patch of hydrophobic residues in the ACE2-binding site that are highly conserved in SARS-CoV-2 variants, explaining its broad neutralization capacity. 87G7 protected mice and hamsters prophylactically against challenge with all current SARS-CoV-2 VOCs and showed therapeutic activity against SARS-CoV-2 challenge in both animal models. Our findings demonstrate that 87G7 holds promise as a prophylactic or therapeutic agent for COVID-19 that is more resilient to SARS-CoV-2 antigenic diversity.

Original languageEnglish
Article numbereabp9312
JournalScience immunology
Volume7
Issue number73
DOIs
Publication statusPublished - Aug 2022

Bibliographical note

Funding: The MANCO project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement no. 101003651). This work made use of the Dutch national e-infrastructure with the support of the SURF Cooperative using grant no. EINF-2453. This research was funded by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) 398066876/GRK 2485/1; BMBF (Federal Ministry of Education and Research) project entitled RAPID (Risk assessment in re-pandemic respiratory infectious diseases), 01KI1723G; and Ministry of Science and Culture of Lower Saxony in Germany (14-76103-184 CORONA-15/20).

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